Despite earlier detection and a lower size of the primary tumors at the time of diagnosis (Nystrom, L. et al., Lancet 341:973-978 (1993); Fletcher, S. W. et al., J. Natl. Cancer Inst. 85:1644-1656 (1993)), associated metastases remain the major cause of breast cancer mortality (Frost, P. & Levin, R., Lancet 339:1458-1461 (1992)). The initial steps of transformation characterized by the malignant cell escape from normal cell cycle controls are driven by the expression of dominant oncogenes and/or the loss of tumor suppressor genes (Hunter, T. & Pines, J., Cell 79:573-582 (1994)).
Tumor progression can be considered as the ability of the malignant cells to leave the primary tumoral site and, after migration through lymphatic or blood vessels, to grow at a distance in host tissue and form a secondary tumor (Fidler, I. J., Cancer Res. 50:6130-6138 (1990); Liotta, L. et al., Cell 64:327-336 (1991)). Progression to metastasis is dependent not only upon transformation but also upon the outcome of a cascade of interactions between the malignant cells and the host cells/tissues. These interactions may reflect molecular modification of synthesis and/or of activity of different gene products both in malignant and host cells. Several genes involved in the control of tumoral progression have been identified and shown to be implicated in cell adhesion, extracellular matrix degradation, immune surveillance, growth factor synthesis and/or angiogenesis (reviewed in, Hart, I. R. & Saini, A., Lancet 339:1453-1461 (1992); Ponta, H. et al., B.B.A. 1198:1-10(1994); Bernstein, L. R. & Liotta, L. A., Curr. Opin. Oncol. 6:106-113 (1994); Brattain, M. G. et al., Curr. Opin. Oncol. 6:77-81 (1994); and Fidler, I. J. & Ellis, L. M., Cell 79:185-188 (1994)).
However, defining the mechanisms involved in the formation and growth of metastases is still a major challenge in breast cancer research (Rusciano, D. & Burger, M. M., BioEssays 14:185-194 (1992); Hoskins, K. & Weber, B. L., Current Opinion in Oncology 6:554-559 (1994)). The processes leading to the formation of metastases are complex (Fidler, I. J., Cancer Res. 50:6130-6138 (1990); Liotta, L. et al., Cell 64:327-336 (1991)), and identifying the related molecular events is thus critical for the selection of optimal treatments.